Carlo Di Lorenzo, M.D.Email: Carlo.Dilorenzo@nationwidechildrens.org

Twitter: @carlodilorenzo1

Functional disorders in pediatric IBD

Disclosures

I have the following financial relationships with the manufacturer(s) of commercial product(s) and/or provider of commercial services discussed in this CME activity:Consultant for: Mahana, Sucampo, Merck, Allergan, QOL Inc., MallinckrodtI do not intend to discuss unapproved/ investigative uses of commercial products/devices in my presentation

The piece noted that “instead of removing diseased sections of the intestine,” for instance, “Crohn’s patients can have a procedure called strictureplasty….

IBD or IBS? Even the AGA gets confused

And NASPGHAN!

https://www.crohnscolitisfoundation.org/what-is-ibd/ibs-vs-ibd

IBS• Anxiety and depression associated with new

onset GI symptoms• GI symptoms associated with development

of psychological disorders de novo• The more psychological symptoms, the

worse the QOL

IBD• Anxiety and depression associated with new

onset GI symptoms• GI symptoms associated with development

of psychological disorders de novo• The more psychological symptoms, the

worse the QOL

IBD• Anxiety and depression associated with new

onset GI symptoms• GI symptoms associated with development

of psychological disorders de novo• The more psychological symptoms, the

worse the QOL

The anxiety epidemic

New York Times, Aug. 17, 2019

Based on the parent report, lifetime diagnosis of anxiety or depression among children aged 6 to 17 years increased from 5.4% in 2003 to 8.4% in 2011–2012. Anxiety and depression were associated with increased risk of co-occurring conditions, health care use, school problems, and having parents with high parenting aggravation

J Dev Behav Pediatr 2018, April 24

Data from CDC

How common are internalizing disorders in children with IBD?

JPGN 2015;60: 30–35

• 93 children with CD: 30% of the youths reported experiencing elevated anxiety symptoms (SCARED score >20), with school anxiety, general anxiety, and separation anxiety symptoms most frequent. • Youth rated with moderate/severe disease activity self-

reported more anxiety symptoms compared with youth with inactive disease. • Greater school anxiety was associated with decreased

well-being, more abdominal pain and diarrhea • Having extraintestinal symptoms was significantly

associated with higher somatic/panic anxiety

374 pts (mean age 18.9 years): Mild anxiety/depressive symptoms were present in 35.2% and severe symptoms in 12.4% of patients. Elevated symptoms of either anxiety (28.3%), depression (2.9%) or both (15.8%) were found. Conclusions: psychological screening is recommended in young IBD patients. Screening facilitates early recognition and psychological treatment. Female patients and patients with active disease are the most vulnerable.

Danielle• 15 year old female with daily periumbilical

abdominal for one year• Pain relieved with passage of loose stools• No weight loss. Able to function, but at times

leaves school early due to the pain• Cousin with IBD (or is it IBS?) • Exam normal. ESR 17, Hct 36, albumin 4.2,

heme (-) stool, calprotectin 98. Colonoscopy reveals no visible change, bx show mild chronic inflammation• IBD or IBS? Both?

Nancy• 15 year old female with ulcerative colitis for 5

years• Chronically on 5-ASA and 6-MP. Off prednisone

for 3 years• Routine visit: c/o early morning periumbilical

cramping and nausea, post-prandial urgency and loose stools. Weight unchanged from last visit

• Exam normal. ESR 14, Hct 39, albumin 4.2, heme (-) stool. Flex sig reveals no visible inflammation, bx reveals mild chronic inflammation• IBD or IBS? Both?

Does it matter?

Do we need to find out if“it is in the head or in the gut”?

“Organification” of IBS• Increased immune activation in response to

infection and stress• Altered mucosal permeability • Sensory nerves hyperexcitability• Different microbiome• Impaired bile acid absorption• Mastcells activation

Control

IBS

IBS

Activated mast cells in IBS

N

N

NN

N

Degranulating

Close proximity (<5 µm) between mast cells and nerves correlates with abdominal pain in IBS

Barbara et al. Gastroenterology 2004;126:693-702

Functional Bowel DisordersThe role of inflammation

Stress and early life events

Acute infection & mucosal inflammation

Low-grade inflammation of neuromuscular layers

Persistent neuromuscular dysfunction

SYMPTOMS!!!!

Role of immune system?Genetic predispositionEnvironmental stressors?

“Functionalization” of IBD?

IBD-IBS

§ Of 3,609 IBD patients, 20% reported IBS § IBD-IBS associated with :

Higher narcotic usePoorer QOLAnxiety, depression, fatigue, sleep problemsReduced social satisfaction

Conclusion: Coexisting IBS-like symptoms among IBD patients in remission are associated with an increased level of fatigue and disease-related worries

• All children were diagnosed with a functional disorder: irritable bowel syndrome (5), functional abdominal pain (2), and functional dyspepsia (1).

• Threshold for pain was lower in CD patients compared to the normal controls.

• 7/8 patients had scores for an anxiety problem.

IBS and IBD: visceral hyperalgesiaFaure C, et al. Inflamm Bowel Dis. 2008;14:1569-74

Is it time to use the term “Irritable inflammatory bowel syndrome” (IIBS) to

refer to this phenomenon?

Back to our cases

Poor correlation between symptoms and objective markers of inflammation

Prospective f/u of 188 enrolled in SONIC trial , with assessment of endoscopic activity at baseline and 26 weeks

“Clinical remission” CDAI <150 (n=136)

“Moderate severity” active CD (CDAI>220)

Complete mucosal healing

56% 29%

Normal CRP 65% 48%Both complete mucosal healing and normal CRP 39% 23%

DDW 2013, abstract 1202

Cremon C et al. AJG 2009; 104:392-400

Problems with calprotectin in IBS-IBD

The “smell test”?

Inflamm Bowel Dis • Volume 24, Number 11, November 2018

Conclusion: Pediatric IBS/FAP could be differentiated from IBD by fecal volatile organic

compounds analysis with high accuracy

Do stress and anxiety cause flares?

Aliment Pharmacol Ther.2018;48:358–369

Clinical Gastroenterology and Hepatology 2016;14:829–835

Stress and flares

Front Pediatr. 2019 Oct 24;7:432

Stress and IBD

Depression and IBD

Mittermaier C, et al. Psychosomatic Medicine 2004; 66:79-84

Stop asking about bloody stools, ask instead about fatigue, sleep quality,

depressive symptoms

Treatment

TreatmentIs it better to immunosuppress a

child with IBS or to treat with cognitive behavioral interventions a child with active IBD?

Mesalamine and IBS

• Randomized, DBPC trial in 20 patients with IBS. Patients randomized to receive placebo or 800 mg mesalamine TID daily for 8 wks

• Mesalamine markedly reduced immune cells as compared with placebo (p=0.0082); this effect was ascribed to an inhibition of mastcells (p=0.0014)

• Mesalamine significantly increased general well-being (p=0.038), but had no significant effects on abdominal pain (p=0.084), bloating (p=0.177) or bowel habits

Corinaldesi et al. Aliment Pharmacol Ther. 2009;30:245-52

Steroids and IBS

Huerta C at al. Pharmacoepidemiol Drug Saf 2003; 12: 583-8

Case-control study of 65,270 pts with at least one use of steroid over 5 years

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Reduced risk of IBS greater among females and after 40 years of age

RR and 95% CI

Nonusers

Low-Mediumdose

Highdose

Predni-solone

Others

Treatment of IBS in the IBD Patient

• Education that not all symptoms are due to IBD

• Use a bio-psycho-social approach• Identify stressors?• Dietary, psychological and

behavioral therapies• Pharmacologic intervention:

Placebo, TCA, SSRI

Methods: 52 consecutive adult patients with Crohn's disease and 20 with ulcerative colitis who received dietary advice about the FODMAP diet. Results: Up to 70% of pts were adherent to the diet. Approximately 50% patients improved (defined as improvement of at least 5 out of 10 in overall symptoms)

Low FODMAP diet in IBDGearry RB, et al. J Crohns Colitis. 2009;3:8-14

We found no significant difference after 4 weeks in change in irritable bowel syndrome severity scores, but significant improvements in specific symptom scores and numbers reporting adequate symptom relief. The low FODMAP diet reduced fecal abundance of microbes (including Bifidobacterium adolescentis) believed to regulate the immune response, compared with the control diet, but had no significant effect on markers of inflammation.

Aliment Pharmacol Ther. 2013; 38(7): 761–771.

Conclusions—This was the first prospective study that has demonstrated a significant effect of a psychological intervention on prolonging clinical remission in patients with quiescent UC

7 sessions of gut-directed HYP or attention control and followed for 1 yr

(Inflamm Bowel Dis 2016;22:694–701)

Compared with the control group, the MI-IBD group reported significantly greater improvements in anxiety, QOL, and mindfulness at after intervention, with reduction in depression and improvements in QOL and mindfulness maintained at 6 months after intervention.

Summary• Internalizing disorders are increasing in

prevalence• Comorbid psychological symptoms are

common in both groups and affect quality of life

• Acute and chronic gut inflammation may lead to abnormalities in gastrointestinal motility and sensation; some pts develop IBS-like symptoms

Summary• Stress may play a role in gut

inflammation• There is no universally accepted test

to differentiate IBS from IBD• Education (for families and medical

professionals) is essential• Treatment should be tailored to the

individual, not to the disease

The end and thank you!